Project 2: Effects of Hypoxia on Cerebral Cortex: Role of Age and Growth Factors in the Response of Cellular and Connectional Elements. Longitudinal studies of preterm infants suggest that hypoxic stress is a dominant factor contributing to neurodevelopmental handicap. The susceptibility of these children to hypoxia is particularly pronounced during the newborn period, when progressive and regressive phenomena are active in the formation of appropriate patterns of cortical circuitry and cell number. We have previously demonstrated that rats reared under chronic hypoxic conditions during the perinatal period have reduce cortical volume, an increase in total cortical cell number and an exuberance of callosal projections. These features are typical of the organization of the immature cerebral cortex and suggest that hypoxia may precociously arrest or delay normal regressive processes which give rise to the mature pattern of cortical organization. We hypothesize that these alterations may be due to an overexpression of growth factors, including members of the FGF family, which are critical in the regulation of neuronal cell number and the stabilization of connectional elements. In Specific Aim 1, the critical period and permanence of the effect of hypoxia will be determined by exposing rats to a hypoxic environment for restricted periods. These animals will then be examined at different post- hypoxic intervals to determine changes in cell number and cortico- cortical connectivity. We will then explore whether growth factor systems play a role in the response of the cerebral cortex to neonatal hypoxia and whether the mechanisms of action of these growth factors include the regulation of cell death or cell proliferation. In Specific Aim 2, we will determine the levels and distribution of growth factors and their receptors within the normoxic and hypoxic brain. In Specific Aim 3, we will measure the number of apoptotic cells by in situ end labeling of DNA fragments, the levels of expression of apoptosis related genes by Western and Northern analyses and the number of proliferative cells by BrdU incorporation to determine whether the increased cell signal transduction within the cortex by the implantation of cells overexpression, respectively, FGF2 or a soluble and inactive form of FGF receptor. These animals will be reared under either normoxic or hypoxic conditions to assess whether changes in FGF expression modify cortical cell number or levels of apoptosis.